Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders in human. In spite of extensive research on the pathogenesis of PD, no effective therapy is available to halt this devastating neurodegenerative process. Recently we have demonstrated that Parkinsonian neurotoxin MPP+ induces the activation of NF-?B in human and mouse glial cells, that NF-?B activation is induced in vivo in the SNpc of PD patients and MPTP-intoxicated mice and that selective inhibition of NF-?B by NBD peptide results in significant protection of nigrostriatal neurons against MPTP-induced neurodegeneration in mice. These mice results suggest that this NF-?B-based therapeutic approach may be useful in PD. As we know mice results are not always translated to humans. Had all mice results been replicated in PD in human, the PD would have been cured long ago. Therefore, we would like to examine the efficacy of NEMO-binding domain peptides in inhibiting the disease process in a monkey model of PD, the best available model for human PD. First, we will investigate if this peptide enters into monkey brain. Second, activation of microglia and astroglia and production of proinflammatory molecules play an important role in the pathogenesis of several neurodegenerative disorders including PD. Our studies will indicate if NBD peptide treatment is capable of inhibiting the activation of microglia and astroglia and attenuating the expression of proinflammatory molecules in MPTP-intoxicated hemiparkinsonian monkeys. Third, it has been shown that nigrostriatal dopaminergic neurons in PD patients as well as in MPTP-intoxicated monkeys disappear. We will investigate if NBD peptide can protect these neurons in MPTP-intoxicated hemiparkinsonian monkeys. Fourth, this proposal will examine if NBD peptide can restore the level of dopamine in the striatum of MPTP-intoxicated monkeys. Fifth, similar to PD, MPTP intoxicated monkeys also display locomotor abnormalities. We will test if NBD peptide can improve locomotor activities in MPTP-intoxicated monkeys. If our mice results are replicated in monkeys, it could be a remarkable advancement in the treatment of PD. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: In spite of extensive research on the pathogenesis of Parkinson's disease (PD), no effective therapy is available to halt this devastating neurodegenerative process. Here we would like to test the efficacy of NBD peptide, a specific inhibitor of induced NF-?B activation, in inhibiting the disease process in a monkey model of PD, the best available model for human PD. Results obtained from this proposal will increase the possibility of treating PD patients with NBD peptides as primary or adjunct therapy. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page